Development of Pathology-activated Drugs for Treatment of Neuropathic Pain

目前治疗神经性疼痛的方法效果不佳。一个可能的原因是目前的治疗只针对单一的生化机制或途径，而慢性疼痛是一个多机制的问题。富马酸盐，如富马酸单甲基（MMF），由于其抗氧化和抗炎的组合特性，在治疗多机制疼痛问题上具有独特的定位。然而，富马酸盐治疗慢性疼痛的风险-收益比是不可接受的，因为它们的胃肠道耐受性差，而且免疫系统不受干扰。本研究项目拟在富马酸酯镇痛疗效文献的基础上，设计新的MMF前药，通过设计非反应性前药提高耐受性。为了减少系统性免疫干扰，将进一步设计前药，仅在疼痛神经轴中ROS/RNS过量产生的地方优先释放活性代谢物MMF。总体目标是开发一种1,2-二羰基前药，优先在病理部位释放MMF，以减轻神经性疼痛，同时减少富马酸盐全身分布引起的不良反应。初步数据表明，抗氧化主调控核因子红细胞2相关因子2 （NRF2）是主要的治疗靶点。使用经过验证的NRF2激活剂和标准护理疗法作为比较，UG3的具体目标是：1)完成1,2-二羰基MMF前体药物的初步表征；2)优化先导化合物，设计和评价备用1,2-二羰基MMF前药；3)评价铅和备用1,2-二羰基MMF前药的安全性和镇痛效果。探索性里程碑将确定一个先导分子和备用分子。这些化合物将在以下UH3期特定目标下通过ind研究推进：4)广泛的候选药物PK/PD表征；5)在已建立的神经性疼痛啮齿动物模型中证明其体内疗效；6)剂量范围的确定，以建立最大耐受剂量（MTD）和心血管，呼吸和胃肠道的安全性和毒性研究；7)建立领导开发团队来完成IND申请。BPN资源将用于CMC的生产和扩大规模，并制定1期临床试验计划。该项目的成功完成将对疼痛病理局部区域的非阿片类药物靶向激活递送（MMF）产生重大影响。部位特异性释放MMF将减少其不良反应，消除以MMF为基础的神经性疼痛治疗的最后障碍。

Current therapeutics for neuropathic pain are poorly efficacious. One likely reason is that current therapies target only a single biochemical mechanism or pathway while chronic pain is a multi-mechanism problem. Fumarates, such as monomethyl fumarate (MMF), are uniquely positioned to treat the multi-mechanism problem of pain due to their combined antioxidant and anti-inflammatory profile. However, the risk-benefit ratio of fumarates is unacceptable for treatment of chronic pain, given their poor gastrointestinal tolerability and indiscriminate immune interference. This research project proposes to build on the documented analgesic efficacy of fumarates by designing new MMF prodrugs that have improved tolerability through design of non-reactive prodrugs. To reduce systemic immune interference, prodrugs will further be designed to preferentially release MMF, the active metabolite, only where ROS/RNS are overproduced in the pain neuraxis. The overall objective is to develop a 1,2-dicarbonyl prodrug that preferentially releases MMF at sites of pathology to alleviate neuropathic pain, while reducing adverse effects caused by systemic distribution of fumarates. Preliminary data indicate that the antioxidant master regulator nuclear factor erythroid 2-related factor 2 (NRF2) is a major therapeutic target. Using validated NRF2 activators and standard of care therapeutics as comparators, the UG3 specific aims are: 1) Complete initial characterization of the lead 1,2-dicarbonyl MMF prodrug; 2) Optimize lead compound, and design and evaluate backup 1,2-dicarbonyl MMF prodrugs; and 3) Characterize safety, validate analgesic efficacy of lead and backup 1,2-dicarbonyl MMF prodrugs. The exploratory milestones will identify a lead and backup molecules. These compounds will be advanced through IND-enabling studies under the following UH3 phase specific aims: 4) Extensive PK/PD characterization of candidates; 5) demonstrate in vivo efficacy in established rodent models of neuropathic pain; 6) Dose range finding to establish maximal tolerated dose (MTD) and cardiovascular, respiratory and gastrointestinal safety and toxicity studies; and 7) establish a Lead Development Team to finalize an IND application. BPN resources will be engaged for CMC manufacture and scale up, and development of a phase 1 clinical trial plan. Successful completion of this project will have major impact by first-in-class target activated delivery of a non-opioid therapeutic agent (MMF) to localized regions of pain pathology. Site-specific release of MMF will reduce its adverse effects, eliminating the final hurdles to MMF- based treatment of neuropathic pain.